About this program
Avdoralimab / IPH5401 is a therapeutic antibody that specifically binds and blocks C5a receptors (C5aR) expressed on subsets of myeloid-derived suppressor cells (MDSC) and neutrophils. Part of the innate immune system, these types of cells promote tumor growth by secreting inflammatory and angiogenic factors. They potently suppress T and NK cells and hamper the activities of PD-1 checkpoint blockers.
C5a, a factor in the complement cascade, is often overexpressed in tumors, where it attracts and activates MDSC and neutrophils in the tumor microenvironment.
Avdoralimab is a fully human antibody that blocks the binding of C5a to C5aR, thereby reducing the accumulation and activation of MDSC and neutrophils in tumors. Treatment with avdoralimab may unleash anti-tumor activities of T cells and NK cells. Preclinical experiments support development of avdoralimab as single agent and in combination with PD-1 checkpoint blockers or other cancer immunotherapies.
Mechanism of action of avdoralimab
In January 2018, Innate Pharma and AstraZeneca entered into a clinical trial collaboration to evaluate the safety and efficacy of the combination of avdoralimab (anti-C5aR) and durvalumab (anti-PD-L1) in a Phase I study for patients with selected solid tumors.
The trial, called STELLAR-001*, started in September 2018.
*STELLAR = SelecTivE bLocking of compLement receptor C5AR to boost immune response and improve cancer outcomes
The dose escalation part of the trial STELLAR-001 is expected to establish a recommended dose regimen of avdoralimab in combination with durvalumab in selected solid tumors. The extension cohort part will assess the safety and efficacy of the combination in:
- Patients with IO-pretreated NSCLC
- Patients with IO-naïve HCC
- Patients with IO-pretreated HCC patients
Based on the data from cohort expansions in NSCLC and IO-naïve HCC, the Company has made the decision to stop enrollment in STELLAR-001.
The Company is pursuing investigator-sponsored trials in chronic spontaneous urticaria (CSU) and bullous pemphigoid (BP) where the C5aR1 pathway has been shown to be strongly involved in the physiopathology of the disease.
Both trials are expected to start in the second half of 2020.
C5a has been implicated in the pathogenesis of ARDS by promoting a proinflammatory environment, through the attraction of neutrophils and stimulation of immune cells such as T and B cells to release cytokines. Avdoralimab blocks C5aR and has the potential to reduce the inflammatory response in the lungs.
End of April 2020, Innate Pharma announced that the first patient was dosed in a randomized, double-blind Phase II clinical trial, evaluating the safety and efficacy of avdoralimab in COVID-19 patients with severe pneumonia.
The trial, named FORCE (FOR COVID-19 Elimination) will be conducted in La Timone Hospital and Nord Hospital in Marseille (Hopitaux Universitaires de Marseille – AP-HM) and in the Hospital Laveran (HIA-Laveran).
The trial is expected to enroll a total of 108 patients (age 18-80) between two cohorts: one cohort of COVID-19 patients with severe pneumonia without acute respiratory distress syndrome (ARDS) at baseline and one cohort of COVID-19 patients with severe pneumonia complicated by ARDS and admitted in ICU at baseline. In each cohort, patients will receive avdoralimab or placebo.
The Phase II trial is supported by an exploratory translational study, EXPLORE COVID-19, which suggests that patients who progress towards severe COVID-19 disease exhibit an activation of the C5a/C5aR pathway.
Carvelli, Demaria, Vély, Batista, Chouaki Benmansour, Fares, Carpentier, Thibult, Morel, Remark, André, Represa, Piperoglou, Cordier, Le Dault, Guervilly, Simeone, Gainnier, Ebbo, Schleinitz, Vivier et al, 2020. Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis Nature Carvelli, Demaria, Vély, Batista, Chouaki Benmansour, Fares, Carpentier, Thibult, Morel, Remark, André, Represa, Piperoglou, Cordier, Le Dault, Guervilly, Simeone, Gainnier, Ebbo, Schleinitz, Vivier et al, 2020. Identification of immune checkpoints in COVID-19 Research Square Pio et al, 2019. Complementing the Cancer-Immunity Cycle Frontiers in Immunology Medler et al, 2018. Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy Cancer Cell Ajona et al, 2017. A Combined PD-1/C5a Blockade Synergistically Protects against Lung Cancer Growth and Metastasis Cancer discovery Liang et al, 2016. The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis Cancer Immunol Res. Hwu et al, 2016. Complementing T-cell Function: An Inhibitory Role of the Complement System in T-cell-Mediated Antitumor Immunity Cancer discovery Wang et al, 2016. Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression Cancer discovery Janelle V et al, 2014. Role of the complement system in NK cell-mediated antitumor T-cell responses Oncoimmunology Kim et al, 2014. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells PNAS Corrales et al, 2012. Anaphylatoxin C5a creates a favorable microenvironment for lung cancer progression J Immunol Markiewski et al, 2008. Modulation of the antitumor immune response by complement Nat Immunol.